Title
Opposing effects of HLA class I molecules in tuning autoreactive <tex>$CD8^{+}$</tex> T cells in multiple sclerosis Opposing effects of HLA class I molecules in tuning autoreactive <tex>$CD8^{+}$</tex> T cells in multiple sclerosis
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Veterinary Sciences
Faculty of Medicine and Health Sciences
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Publication type
article
Publication
London ,
Subject
Pharmacology. Therapy
Source (journal)
Nature medicine. - London, 1995, currens
Volume/pages
14(2008) :11 , p. 1227-1235
ISSN
1078-8956
1546-170X
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Abstract
The major known genetic risk factors in multiple sclerosis reside in the major histocompatibility complex (MHC) region. Although there is strong evidence implicating MHC class II alleles and CD4+ T cells in multiple sclerosis pathogenesis, possible contributions from MHC class I genes and CD8+ T cells are controversial. We have generated humanized mice expressing the multiple sclerosisassociated MHC class I alleles HLA-A*0301 (encoding human leukocyte antigen-A3 (HLA-A3)) and HLA-A*0201 (encoding HLA-A2) and a myelin-specific autoreactive T cell receptor (TCR) derived from a CD8+ T cell clone from an individual with multiple sclerosis to study mechanisms of disease susceptibility. We demonstrate roles for HLA-A3restricted CD8+ T cells in induction of multiple sclerosislike disease and for CD4+ T cells in its progression, and we also define a possible mechanism for HLA-A*0201mediated protection. To our knowledge, these data provide the first direct evidence incriminating MHC class I genes and CD8+ T cells in the pathogenesis of human multiple sclerosis and reveal a network of MHC interactions that shape the risk of multiple sclerosis.